PROJECT SUMMARY/ABSTRACT Tuberculous meningitis (TBM) is the most serious form of TB. Outcomes are particularly severe amongst HIV- infected patients, in whom the mortality approaches 60%, and survivors are frequently left with substantial neurological disability. One reason for poor outcomes is inadequate drug concentrations in the cerebrospinal fluid (CSF), including with standard doses (10mg/kg) of rifampicin, the key antituberculosis agent. Several lines of evidence support the hypothesis that outcomes in TBM may be improved with the use of higher rifampicin doses and the addition of linezolid, which has excellent CSF penetration. This forms partial rationale for a Phase 2a randomized controlled trial (LASER-TBM) which will evaluate the safety of 35mg/kg rifampicin and linezolid in South Africans with HIV-associated TBM (n = 100) to inform larger efficacy trials. However, knowledge of high dose rifampicin and linezolid for TBM is limited. First, plasma and CSF pharmacokinetics (PK) as well as exposure-response relationships, important for dose optimization, are inadequately defined. Specifically, the influence of dynamic changes in protein levels on rifampicin CSF concentrations is unknown. Second, it is unclear whether oral high dose rifampicin achieves similar exposures to intravenous therapy, planned for efficacy trials. Third, there is a drug-drug interaction between rifampicin and linezolid that may reduce the therapeutic benefit of linezolid. The scientific goal of this proposal is to address these knowledge gaps by characterizing the PK of high dose rifampicin and linezolid in the LASER-TBM trial, with the objective of informing the therapeutic approach for future efficacy trials and clinical practice. The specific aims are to: (1) describe plasma and CSF PK of linezolid and high dose rifampicin, including protein-unbound concentrations, and evaluate relationships between exposure, efficacy and toxicity; (2) investigate the drug-drug interaction between linezolid and rifampicin to provide a robust estimation of rifampicin effects on linezolid exposure; and (3) compare plasma and CSF exposures of high dose oral versus intravenous rifampicin to support use of oral rifampicin in clinical trials and in programmatic settings. This proposal is responsive to areas of critical need in South Africa: research that is highly relevant to regional health priorities; and career development of a local clinician-scientist. Dr. Sean Wasserman is an Infectious Diseases physician at the University of Cape Town with a career goal to independently conduct research that informs clinical practice and ultimately reduces the burden of disease. The proposed activities are well-aligned to his PhD on optimizing use of linezolid for TB through PK studies. A comprehensive career development plan comprising structured activities and mentorship opportunities will facilitate Dr. Wasserman?s training goals to acquire advanced analytical skills in pharmacometrics, including spatial quantitation of drugs, and experience in clinical trial design, conduct, and analysis. This K43 award will position him to build an independent program of research in TB and conduct pharmacometric studies and clinical trials that impact on health outcomes in sub-Saharan Africa.